Method for Suppressing Bitterness of Quinoline Derivative

ABSTRACT

The present invention provides a method for suppressing bitterness of a quinoline derivative.

TECHNICAL FIELD

The present invention relates to a method for suppressing bitterness ofa medicine.

BACKGROUND ART

4-(3-Chloro-4-(cydopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamide(hereinafter also referred to as Compound 1 or lenvatinib) or a saltthereof, which is a quinoline derivative having an antiangiogeniceffect, is known (Patent Literature 1).

As a pharmaceutical composition comprising Compound 1 or a salt thereof,there is known a pharmaceutical composition comprising Compound 1 or asalt thereof and (i) a compound, a 5% (w/w) solution or suspension ofwhich has a pH of 8 or more and/or (ii) a silicic acid to reduce adegradation under humidified and heated conditions or inhibit a gelationon a surface of the pharmaceutical composition (Patent Literature 2).

Besides, as a pharmaceutical composition excellent in dissolutionproperties of Compound 1 and stable through long-term storage, apharmaceutical composition comprising (1) Compound 1 or a salt thereof;and (2) a basic substance is known (Patent Literature 3).

Furthermore, there is known a composition comprising a pharmacologicallyactive ingredient of an organic sulfonate, a disintegrating agent and awater-soluble salt, a 2.5% aqueous solution of which has a pH of 3 to 9(Patent Literature 4).

CITATION LIST Patent Literature

[Patent Literature 1] U.S. Patent Application Publication No.2004/0053908

[Patent Literature 2] U.S. Patent Application Publication No.2008/0214604

[Patent Literature 3] U.S. Patent Application Publication No.2012/0077842

[Patent Literature 4] U.S. Patent Application Publication No.2008/0214557

SUMMARY OF INVENTION Technical Problem

Usually, when a pharmaceutical composition is administered to a patient,a pharmaceutical composition such as a capsule dissolved or suspended inwater or the like is administered in some cases from the viewpoint ofmedication compliance. If a drug having bitterness dissolved orsuspended in water or the like is administered to a patient, however, itis apprehended that the patient may have trouble taking the drug due tothe bitterness, and this tendency is increased if the patient is achild. Besides, when a pharmaceutical composition is administered to achild, an administration form that can be easily swallowed, such as asuspension, is sometimes employed, but due to the size of the digestivetract of the child, there is an upper limit in the amount of a solventused for the suspension. On the other hand, due to the physicalproperties of an active pharmaceutical ingredient such as consistencyand solubility, not only the bitterness but also the activepharmaceutical ingredient contained in the suspension may remain in avessel, and thus, the recovery may not be sufficient in some cases.

Solution to Problem

The present inventors have found that Compound 1 or a pharmaceuticallyacceptable salt thereof has bitterness. As a result of earnest studies,the present inventors have found that the bitterness of Compound 1 orthe pharmaceutically acceptable salt thereof can be suppressed by mixinga basic substance such as calcium carbonate with Compound 1 or thepharmaceutically acceptable salt thereof. Besides, the present inventorshave found that if an administration method comprising: 1) suspending,in an aqueous solvent in a vessel, a pharmaceutical compositioncomprising Compound 1 or a pharmaceutically acceptable salt thereof anda basic substance; 2) administering a suspension obtained in 1) from thevessel to a patient 3) rinsing the vessel with an aqueous solvent; and4) administering a rinsing solution obtained in 3) to the patient isemployed, the suspension of Compound 1 can be administered to a child athigh recovery without causing the child to feel bitterness and in aliquid amount administrable to the child.

Specifically, the present invention provides the following [1] to [33]:

[1] A method for suppressing bitterness of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamide,comprising mixing4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof and a basic substance.[2] The method according to [1], wherein 0.01 to 50 parts by weight ofthe basic substance is mixed per 1 part by weight of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.[3] The method according to [1], wherein 0.16 to 80 mol of the basicsubstance is mixed per 1 mol of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.[4] The method according to any one of [1] to [3], wherein the basicsubstance is a basic oxide, a basic carbonate or a basic hydroxide.[5] The method according to any one of [1] to [3], wherein the basicsubstance is calcium carbonate or magnesium oxide.[6] The method according to any one of [1] to [3], wherein the basicsubstance is calcium carbonate.[7] The method according to any one of [1] to [6], wherein thepharmaceutically acceptable salt is a mesylate.[8] A pharmaceutical composition, comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance inan amount effective for suppressing bitterness.[9] A pharmaceutical composition, comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, the pharmaceuticalcomposition comprising means for mixing a basic substance forsuppressing bitterness.[10] A pharmaceutical composition, comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof and a basic substance, thepharmaceutical composition having bitterness suppressed.[11] The pharmaceutical composition according to any one of [8] to [10],comprising 0.01 to 50 parts by weight of the basic substance per 1 partby weight of4-(3-chloro-4-(cydopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.[12] The pharmaceutical composition according to any one of [8] to [10],wherein 0.16 to 80 mol of the basic substance is mixed per 1 mol of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.[13] The pharmaceutical composition according to any one of [8] to [12],wherein the basic substance is a basic oxide, a basic carbonate or abasic hydroxide.[14] The pharmaceutical composition according to any one of [8] to [12],wherein the basic substance is calcium carbonate or magnesium oxide.[15] The pharmaceutical composition according to any one of [8] to [12],wherein the basic substance is calcium carbonate.[16] The pharmaceutical composition according to any one of [8] to [15],wherein the pharmaceutically acceptable salt is a mesylate.[17] The pharmaceutical composition according to any one of [8] to [16],in a dosage form of an orally disintegrating tablet, a chewablepreparation, an effervescent tablet, a dispersible tablet, a solubletablet, a syrup, a preparation for a syrup, a troche, or an oral liquidpreparation.[18] The pharmaceutical composition according to any one of [8] to [16],being a preparation that can be suspended in an aqueous solvent upon anadministration to prepare a suspension.[19] A bitterness suppressing agent, comprising a basic substance, for4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof.[20] The bitterness suppressing agent according to [19], wherein thebasic substance added is in an amount of 0.01 to 50 parts by weight per1 part by weight of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.[21] The bitterness suppressing agent according to [19], wherein thebasic substance added is in an amount of 0.16 to 80 mol per 1 mol of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.[22] The bitterness suppressing agent according to any one of [19] to[21], wherein the basic substance is a basic oxide, a basic carbonate ora basic hydroxide.[23] The bitterness suppressing agent according to any one of [19] to[21], wherein the basic substance is calcium carbonate or magnesiumoxide.[24] The bitterness suppressing agent according to any one of [19] to[21], wherein the basic substance is calcium carbonate.[25] The bitterness suppressing agent according to any one of [19] to[24], wherein the pharmaceutically acceptable salt is a mesylate.[26] A method for administering a suspension comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance,the method comprising: 1) suspending, in an aqueous solvent in a vessel,a pharmaceutical composition comprising 1 to mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof, and the basicsubstance; 2) administering a suspension obtained in 1) to a patientfrom the vessel; 3) rinsing the vessel with an aqueous solvent; and 4)administering a rinsing solution obtained in 3) to the patient.[27] The method according to [26], wherein the 1) comprises: i) pouringthe aqueous solvent in the vessel, ii) allowing the vessel to stand; andiii) shaking the vessel.[28] The method according to [26] or [27], wherein the pharmaceuticalcomposition is suspended in 1 to 10 mL of the aqueous solvent in 1).[29] The method according to [28], wherein the pharmaceuticalcomposition is suspended in about 3 mL of the aqueous solvent in 1).[30] The method according to [26], wherein the vessel is rinsed with 1to 10 mL of the aqueous solvent in 3).[31] The method according to [30], wherein the vessel is rinsed withabout 2 mL of the aqueous solvent in 3).[32] A method for treating a cancer by administering a suspensioncontaining 1 to 24 mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance.[33] A method for treating a cancer, comprising administering asuspension comprising 1 to mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance,the method comprising: 1) suspending, in an aqueous solvent in a vessel,a pharmaceutical composition comprising 1 to 24 mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof, and the basicsubstance; 2) administering a suspension obtained in 1) to a patientfrom the vessel; 3) rinsing the vessel with an aqueous solvent; and 4)administering a rinsing solution obtained in 3) to the patient.

Advantageous Effects of Invention

Compound 1 or a pharmaceutically acceptable salt thereof is known as ananticancer agent for thyroid cancer and the like, and a cancer can betreated without causing a patient to feel bitterness upon drugadministration by the method of the present invention.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram illustrating relative comparison of bitterness oflenvatinib mesylate and quinine hydrochloride.

FIG. 2 is a diagram illustrating concentration dependence of thebitterness suppressing effect of calcium carbonate.

FIG. 3 is a diagram illustrating concentration dependence of thebitterness suppressing effect of magnesium oxide.

FIG. 4 is a diagram illustrating the bitterness suppressing effect ofvarious polymers.

FIG. 5 is a diagram illustrating the bitterness suppressing effect ofvarious low molecular weight compounds.

FIG. 6 is a diagram illustrating the bitterness suppressing effect of alenvatinib mesylate-containing composition.

FIG. 7 is a diagram illustrating the bitterness suppressing effect ofrespective components of the lenvatinib mesylate-containing composition.

FIG. 8 is a diagram illustrating results of a dissolution test of orallydisintegrating tablets.

FIG. 9 is a diagram illustrating the bitterness suppressing effect of alenvatinib mesylate-containing composition.

FIG. 10 is a diagram illustrating the bitterness suppressing effect ofvarious low molecular weight compounds.

FIG. 11 is a diagram illustrating the bitterness suppressing effect ofvarious low molecular weight compounds.

FIG. 12 is a diagram illustrating the bitterness suppressing effect ofvarious silicic acid compounds.

DESCRIPTION OF EMBODIMENTS

Herein, a basic substance may be a low molecular weight compound or ahigh molecular weight compound as long as it is a substance exhibitingbasicity, preferable examples include a basic oxide, a basic carbonate,a basic hydroxide or a sodium salt of a polymer having a carboxyl group,and it is more preferably calcium carbonate, magnesium carbonate,potassium carbonate, magnesium oxide, magnesium hydroxide, sodiumcarboxymethyl starch or croscarmellose sodium, further preferablycalcium carbonate or magnesium oxide, and most preferably calciumcarbonate.

Preferably 0.01 to 50 parts by weight, more preferably 0.03 to 10 partsby weight, and most preferably 0.05 to 5 parts by weight of the basicsubstance is mixed per 1 part by weight of a compound 1.

When the basic substance is a low molecular weight compound, preferably0.16 to 80 mol, more preferably 0.3 to 60 mol, and most preferably 0.5to 40 mol of the basic substance is mixed per 1 mol of Compound 1.

Herein, a pharmaceutically acceptable salt means a hydrochloride, ahydrobromide, a tosylate, a sulfate, a mesylate or an esylate, and ispreferably a mesylate.

Herein, the “bitterness” of Compound 1 or the pharmaceuticallyacceptable salt thereof is measured by the following method. A solutionof Compound 1 at a concentration of 8 mg/mL as a free form is preparedby dissolving Compound 1 or the pharmaceutically acceptable salt thereofin a 10 mM potassium chloride aqueous solution. To the thus obtainedsolution, an additive is added if necessary, and the resultant isstirred for 30 minutes and then centrifuged to give a liquid phasecomponent. The bitterness of the liquid phase component is measuredusing a taste sensor (AC0) for measuring bitterness, and the thusobtained value is used as a bitterness index.

Herein, the term “suppress the bitterness” of Compound 1 or thepharmaceutically acceptable salt thereof means that as measured“bitterness” according to the above-described method, the relative ratioof a measured value of a sample obtained by adding an additive into acontrol, which comprising Compound 1 or the pharmaceutically acceptablesalt thereof, to a measured value of the control is less than 100%, andpreferably 70% or less. Here, the control comprising Compound 1 or thepharmaceutically acceptable salt thereof may be Compound 1 itself or thepharmaceutically acceptable salt thereof itself, or may be a mixturealso comprising an additional component (such as a capsule) ifnecessary.

A pharmaceutical composition of the present invention is notparticularly limited as long as it is a preparation in which thebitterness of Compound 1 or the pharmaceutically acceptable salt thereofmay possibly be felt in a usual administration method or in anadministration method comprising dissolving or suspending in water orthe like without impairing a specific function such as an entericproperty. Examples of such a preparation include an orally administeredpreparation and a preparation applied to oral cavity described in TheJapanese Pharmacopoeia, Sixteenth Edition, General Rules forPreparations, and specific examples include a tablet, an orallydisintegrating tablet, a chewable preparation, an effervescent tablet, adispersible tablet, a soluble tablet, a powder, a granule, a capsule, asyrup, a preparation for a syrup, a troche, an oral liquid preparation(such as a suspension) and an oral jelly preparation. Examples of apreferable form include an orally disintegrating tablet, a chewablepreparation, an effervescent tablet, a dispersible tablet, a solubletablet, a syrup, a preparation for a syrup, a troche and an oral liquidpreparation, which stay hi oral cavity for a comparatively long periodof time and hence possibly cause a patient to feel the bitterness.Besides, even a dosage form of a capsule or the like can be included inthe preferable form if an oral liquid preparation can be prepared fromthe preparation at time of use using a solvent such as water.

The pharmaceutical composition of the present invention can be producedby any of known methods such as methods described in The JapanesePharmacopoeia, Sixteenth Edition, General Rules for Preparations. Forexample, a granule can be produced by adding, if necessary, a dilutingagent, a binding agent, a disintegrator, a solvent or the like toCompound 1 or the pharmaceutically acceptable salt thereof; andsubjecting the resultant to stirring granulation, extrusion granulation,oscillating granulation, fluidized bed granulation, spray granulation orthe like. A core substance of a purified sucrose spherical granule, alactose-crystalline cellulose spherical granule, a sucrose-starchspherical granule or a granular crystalline cellulose may be coated withan epipastic comprising an additive such as water, sucrose,hydroxypropylcellulose, methylcellulose or polyvinylpyrrolidone. Theresultant may be further sized or ground. When the pharmaceuticalcomposition of the present invention is suspended in an aqueous solventsuch as water at time of use and then administered, it is possible toadminister a suspension prepared by suspending a mixture (including adosage form such as a tablet or a capsule) of 1 to 24 mg of Compound 1or the pharmaceutically acceptable salt thereof with a basic substancein an aqueous solvent in a vessel such as a vial, a syringe or a syringeequipped with a nasogastric tube (NG tube). The amount of the aqueoussolvent used for the suspension (which can be a sweet drink such as anapple juice according to patients preference) is preferably 1 to 10 mL,more preferably 2 to 5 mL and further preferably about 3 mL. At the timeof suspending, it is preferable to allow the mixture to stand still fora while, preferably about 10 minutes, after adding the aqueous solvent,and then to shake the resultant for a while, preferably about 3 minutes.Besides, in view of definitely administering Compound 1 or thepharmaceutically acceptable salt thereof, after administering thesuspension, the vessel used for the suspension may be rinsed with 1 to10 mL, more preferably 1 to 5 mL and further preferably about 2 mL of anaqueous solvent, and the resultant rinsing solution may be furtheradministered. Here, a numerical value with the term “about” encompassesa numerical value obtained by rounding off to the nearest whole number,and for example, “about 3” corresponds to a range of 2.5 to 3.4.

A list of reagents used in preparation and bitterness measurement ofexamples and comparative examples is shown in Table 1.

TABLE 1 Molecular Component Weight Manufacturer Grade/Product NamePotassium 74.55 Wako Pure G.R. Chloride Chemical Industries, Ltd.L-Tartaric 150.09 Wako Pure G.R. Acid Chemical Industries, Ltd. EthanolWako Pure G.R. Chemical Industries, Ltd. 2M Hydrochloric Kanto Chemical2 mol/L Hydrochloric Acid Aqueous Co., Inc. Acid (2M) Solution Quinine396.91 Wako Pure E.P. Hydrochloride Chemical Dihydrate Industries, Ltd.Lenvatinib 522.96 Eisai Co., Mesylate Ltd. Calcium 100.09 Bihoku FunkaPrecipitated Calcium Carbonate Kogyo Co., Carbonate A Ltd. Magnesium40.3 Kyowa Chemical Magnesium Oxide, Oxide Industry Co., Japanese Ltd.Pharmacopoeia Magnesium 84.32 Kyowa Chemical (Heavy) Magnesium CarbonateIndustry Co., Carbonate, Japanese Ltd. Pharmacopoeia Potassium 138.21Wako Pure G.R. Carbonate Chemical Industries, Ltd. Sodium Chloride 58.44Wako Pure G.R. Chemical Industries, Ltd. Magnesium 203.30 Wako Pure G.R.Chloride Chemical Hexahydrate Industries, Ltd. Calcium Chloride 110.98Wako Pure G.R. Chemical Industries, Ltd. Ferric Chloride 270.30 WakoPure G.R. Hexahydrate Chemical Industries, Ltd. Magnesium 58.32 KyowaChemical Kyowa Suimag Hydroxide Industry Co., Ltd. Carmellose GotokuChemical ECG-505 Calcium Co., Ltd. Sodium JRS Pharma ExplotabCarboxymethyl Starch Carmellose Gotoku Chemical NS-300 Co., Ltd.Croscarmellose FMC Inter- Ac-Di-Sol Sodium national Inc. DriedMethacrylic Evonik Rohm Eudragit L100-55 Acid Copolymer GmbH LDHypromellose Shin-Etsu AQOAT AS-HF Acetate Succinate Chemical Co., Ltd.Aminoalkyl Evonik Rohm Eudragit EPO Methacrylate GmbH Copolymer EMannitol Rocket Japan Pearlitol 50C Co., Ltd. Crystalline Asahi KaseiCeolus PH-101, Cellulose Chemicals Japanese (PH101) CorporationPharmacopoeia Hydroxypropyl- Nippon Soda HPC-L cellulose Co., Ltd.Low-substituted Shin-Etsu L-HPC LH-21 Hydroxypropyl- Chemical celluloseCo., Ltd. Crystalline Asahi Kasei Ceolus PH-102, Cellulose ChemicalsJapanese (PH102) Corporation Pharmacopoeia Talc Matsumura Hi-Filler #17Sangyo Co., Ltd.

Test Example 1: Relative Comparison of Bitterness Between LenvatinibMesylate and Quinine Hydrochloride

An apparatus and solutions used for the bitterness measurement are shownin Table 2, and measurement conditions for a sample using a tasteperception apparatus are shown in Table 3. As a blank solution forcorrection, a 10 mM potassium chloride aqueous solution was subjected tothe measurement. Measurement samples of Reference Examples 1 to 9 wererespectively prepared by dissolving respective components shown in Table4 in a 10 IBM potassium chloride aqueous solution. The measurement withthe taste perception apparatus was performed four times on each sample,and merely three results of the second to fourth measurements were usedfor analysis. Relative bitterness to Reference Example 7 was calculatedin accordance with the following expression, and an average of the threemeasurement values is shown in Table 4 and FIG. 1. It is noted that therelative bitterness was calculated using merely data obtained through aseries of continuous measurements.

Relative bitterness to Reference Example 7(%)=(Measured value of eachsample−Measured value of 10 mM potassium chloride aqueoussolution)/(Measured value of Reference Example 7−Measured value of 10 mMpotassium chloride aqueous solution)×100%

As a result, it was found that the relative bitterness of ReferenceExample 1 and Reference Example 2 to Reference Example 7 was 100% ormore. Accordingly, it was determined that an aqueous solution oflenvatinib mesylate at a concentration of 1.225 mg/mL or more are morebitter than a 0.1 mM quinine hydrochloride aqueous solution.

TABLE 2 Measurement Apparatus Taste Perception Apparatus (SA402, AnritsuCorporation) Measuring Electrode AC0 Sensor (Intelligent SensorTechnology, Inc.) Reference Electrode Ag/AgCl Electrode Sample SolutionLiquid 10 mM Potassium Chloride Aqueous Solution Reference Liquid 30 mMPotassium Chloride, 0.3 mM L-Tartaric Acid Aqueous Solution WashingSolution 0.1M Hydrochloric Acid Solution (Solvent: water/ethanol = 70/30[v/v] mixture)

TABLE 3 Treatment Step Sensor Treatment Method 1 (Washing 1) Washmeasurement sensor with washing solution for 90 seconds 2 (Washing 2)Wash measurement sensor with reference solution for 240 seconds 3(Washing 3) Wash measurement sensor with reference solution for 240seconds 4 (Stabilization Set potential obtained after immersingmeasurement and Measurement sensor in reference solution for 30 secondsas of Origin) origin for measurement 5 (Pretreatment) Immersemeasurement sensor in measurement sample for 30 seconds 6 (Rinsing 1)Rinse measurement sensor with reference solution for 3 seconds 7(Rinsing 2) Rinse measurement sensor with reference solution for 3seconds 8 (Measurement) Measure potential after immersing measurementsensor in reference solution for 30 seconds

TABLE 4 Refer- Refer- Refer- Refer- ence ence ence ence Exam- Exam-Exam- Exam- ple 1 ple 2 ple 3 ple 4 Quinine Hydrochloride Dihydrate (mM)Lenvatinib 12.25 1.225 0.123 0.012 Mesylate (mg/mL) Relative 446% 117%68% 24% Bitterness to Reference Example 7 (%) Refer- Refer- Refer-Refer- Refer- ence ence ence ence ence Exam- Exam- Exam- Exam- Exam- ple5 ple 6 ple 7 ple 8 ple 9 Quinine 1.00 0.30 0.10 0.030 0.010Hydrochloride Dihydrate (mM) Lenvatinib Mesylate (mg/mL) Relative 254%174% 100% 53% 27% Bitterness to Reference Example 7 (%)12.25 mg/mL of lenvatinib mesylate is equivalent to 10 mg/mL of a freeform of lenvatinib.

Test Example 2: Concentration Dependency of Bitterness SuppressingEffect of Calcium Carbonate

Measurement samples of Examples 1 to 6 and Comparative Example 1 wereprepared in the following manner, and the bitterness was measured byemploying the same apparatus and method as those of Test Example 1.

(1) Lenvatinib mesylate was dissolved in a 10 mM potassium chlorideaqueous solution to a concentration of 9.8 mg/mL.

(2) To the aqueous solution prepared in (1), components other than thelenvatinib mesylate were added to attain a composition shown in Table 5,and the resultant was stirred for 30 minutes with a stirrer.

(3) The resultant was subjected to centrifugation using a centrifugeunder conditions of gravitational acceleration of 20000 g or more for 20minutes, and a supernatant solution was collected as a measurementsample. If the separation of the supernatant portion was found to beinsufficient by visual check, the centrifugation was further performedunder conditions of gravitational acceleration of 20000 g or more for 20minutes, and then the supernatant solution was collected as themeasurement sample. In Comparative Example 1, no solid component wasadded to the aqueous solution prepared in (1), and hence the aqueoussolution of (1) was directly used as the measurement sample withoutperforming the centrifugation.

The measurement with the taste perception apparatus was performed fourtimes on each sample, and three measurement results of the second tofourth measurements were used for the analysis. The relative bitternessto Comparative Example 1 was calculated in accordance with the followingequation, and an average of the three measured values is shown in Table5 and FIG. 2. It is noted that the relative bitterness was calculatedusing merely data obtained through a series of continuous measurements.

Relative bitterness to Comparative Example 1=(Measured value of eachsample−Measured value of 10 mM potassium chloride aqueoussolution)/(Measured value of Comparative Example 1−Measured value of 10mM potassium chloride aqueous solution)×100%

As a result, it was found that the relative bitterness to ComparativeExample 1 was decreased as the amount of potassium carbonate to be addedwas increased, and the relative bitterness of Examples 1 to 4 was foundto be 70% or less.

TABLE 5 Comparative Example 1 Example 2 Example 3 Example 4 Example 5Example 6 Example 1 Lenvatinib Mesylate 9.8 9.8 9.8 9.8 9.8 9.8 9.8(mg/mL) Calcium Carbonate 26.4 2.64 1.32 0.66 0.26 0.026 (mg/mL) MolarRatio 14.1 1.41 0.70 0.35 0.14 0.01 (Additive/Lenvatinib Mesylate)Relative Bitterness to 46% 44% 43% 66% 80% 92% 100% Comparative Example1 (%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

Test Example 3: Concentration Dependency of Bitterness SuppressingEffect of Magnesium Oxide

In the same manner as in Test Example 2, measurement samples of Examples7 to 12 and Comparative Example 1 respectively having compositions shownin Table 6 were prepared to measure the bitterness of the samples.

As a result, it was found, as illustrated in FIG. 3, that the relativebitterness to Comparative Example 1 was decreased as the amount ofmagnesium oxide to be added was increased, and the relative bitternessof Examples 7 to 11 was found to be 70% or less.

TABLE 6 Example Example Example Comparative Example 7 Example 8 Example9 10 11 12 Example 1 Lenvatinib Mesylate 9.8 9.8 9.8 9.8 9.8 9.8 9.8(mg/mL) Magnesium Oxide 26.4 2.64 1.32 0.66 0.26 0.026 (mg/mL) MolarRatio 35.0 3.50 1.75 0.87 0.35 0.03 (Additive/Lenvatinib Mesylate)Relative Bitterness to 16% 12% 9% 7% 44% 89% 100% Comparative Example 1(%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

Test Example 4: Bitterness Suppressing Effect of Various Polymers

In the same manner as in Test Example 2, measurement samples of Examples13 to 14 and Comparative Examples 1 to 6 respectively havingcompositions shown in Table 7 were prepared to measure the bitterness ofthe samples.

As a result, it was found, as illustrated in FIG. 4, that the relativebitterness to Comparative Example 1 of Examples 13 and 14 eachcontaining a sodium salt of a polymer having a carboxyl group was 70% orless.

TABLE 7 Comp. Comp Comp Comp Comp Comp Ex 1 Ex 2 Ex 13 Ex 3 Ex 14 Ex 4Ex 5 Ex 6 Lenvatinib Mesylate 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 (mg/mL)Carmellose Calcium 13.2 (mg/mL) Sodium Carboxymethyl 13.2 Starch (mg/mL)Carmellose (mg/mL) 13.2 Croscarmellose Sodium 13.2 (mg/mL) DriedMethacrylic Acid 13.2 Copolymer LD (mg/mL) Hypromellose Acetate 13.2Succinate (mg/mL) Aminoalkyl 13.2 Methacrylate Copolymer E (mg/mL)Relative Bitterness to 100% 122% 65% 109% 62% 113% 109% 160% ComparativeExample 1 (%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

Test Example 5: Bitterness Suppressing Effect of Various Low MolecularWeight Compounds

In the same manner as in Test Example 2, measurement samples of Examples15 to 17 and Comparative Examples 1 and 7 to 10 respectively havingcompositions shown in Table 8 were prepared to measure the bitterness ofthe samples.

As a result, it was found, as illustrated in FIG. 5, that the relativebitterness to Comparative Example 1 of Examples 15 to 17 each containinga basic compound was 70% or less.

TABLE 8 Comp Comp Comp Comp Comp Ex 1 Ex 15 Ex 16 Ex 7 Ex 8 Ex 9 Ex 10Ex 17 Lenvatinib Mesylate (mg/mL) 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8Magnesium Carbonate 1.11 (mg/mL) Potassium Carbonate (mg/mL) 1.81 SodiumChloride (mg/mL) 0.77 Magnesium Chloride 2.67 Hexahydrate (mg/mL)Calcium Chloride (mg/mL) 1.46 Ferric Chloride Hexahydrate 3.55 (mg/mL)Magnesium Hydroxide 0.77 (mg/mL) Molar Ratio 0.70 0.70 0.70 0.70 0.700.70 0.70 (Additive/Lenvatinib Mesylate) Relative Bitterness to 100% 52%17% 96% 83% 83% 89% 37% Comparative Example 1 (%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

Test Example 6: Bitterness Suppressing Effect of Composition ComprisingLenvatinib Mesylate

In the same manner as in Test Example 2, the bitterness of Example 18and Comparative Example 1 respectively having compositions shown inTable 9 was measured.

The measurement sample of Example 18 was prepared by the followingmethod: The amounts of respective raw materials used in preparation of asized granule are shown in Table 10. Lenvatinib mesylate and calciumcarbonate were charged and mixed in a vertical granulator. To thusobtained mixture, mannitol, crystalline cellulose (PH101) andlow-substituted hydroxypropylcellulose were added to be mixed in thevertical granulator. To the resultant mixture, an aqueous solution ofhydroxypropylcellulose and an appropriate amount of purified water weregradually added in this order under stirring. After completing theaddition, the resultant was further stirred in the vertical granulatorto obtain a granulated granule. The granulated granule was dried using afluidized bed with an inlet air temperature set to 70° C., and theresultant was sized using a Comil equipped with a screen having a poresize of 1 mm to obtain a sized granule. The sized granule, crystallinecellulose (PH102) and talc were mixed in a tumbler mixer to obtain acomposition comprising lenvatinib mesylate, the composition of which isshown in Table 9. After adding a 10 mM potassium chloride aqueoussolution to the composition comprising lenvatinib mesylate to aconcentration shown in Table 9, the resultant was stirred for 30 minuteswith a stirrer. After stirring, the centrifugation operation describedin (3) of Test Example 2 was performed to collect a supernatant portionas a measurement sample.

As a result, it was found that the relative bitterness of Example 18 toComparative Example 1 was 70% or less.

TABLE 9 Comparative Example 1 Example 18 Lenvatinib Mesylate (mg/mL) 9.89.8^(a)) Calcium Carbonate (mg/mL) 26.4^(a)) Mannitol (mg/mL) 7.0^(a))Crystalline Cellulose (PH101) (mg/mL) 8.0^(a)) Hydroxypropylcellulose(mg/mL) 2.4^(a)) Low-substituted Hydroxypropylcellulose 20.0^(a))(mg/mL) Crystalline Cellulose (PH102) (mg/mL) 4.0 Talc (mg/mL) 2.4Relative Bitterness to Comparative 100% 20% Example 1 (%)9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.a) is equivalent to 73.6 mg of the sized granule

TABLE 10 Granule for Example 18 (g) Lenvatinib Mesylate 2450 CalciumCarbonate 6600 Mannitol 1750 Crystalline Cellulose (PH101) 2000Hydroxypropylcellulose 600 Low-substituted Hydroxypropylcellulose 5000

Test Example 7: Bitterness Suppressing Effect of Each Component ofLenvatinib Mesylate-Containing Composition

Compositions of measurement samples and measurement results of therelative bitterness of Example 19 and Comparative Examples 1 and 11 to15 to Comparative Example 1 are shown in Table 11 and FIG. 7. Themeasurement of the relative bitterness was performed in the same manneras in Test Example 2. In this examination, the bitterness suppressingeffect of each component of the lenvatinib mesylate-containingcomposition of Example 18 was evaluated.

As a result, it was found, as illustrated in FIG. 7, that the relativebitterness to Comparative Example 1 of Example 19 containing calciumcarbonate was 70% or less.

TABLE 11 Comp Comp Comp Comp Comp Comp Ex 1 Ex 19 Ex 11 Ex 12 Ex 13 Ex14 Ex 15 Lenvatinib Mesylate (mg/mL) 9.8 9.8 9.8 9.8 9.8 9.8 9.8 CalciumCarbonate (mg/mL) 26.4 Mannitol (mg/mL) 70 Crystalline Cellulose (PH101)8.0 (mg/mL) Hydroxypropylcellulose 2.4 (mg/mL) Low-substituted 20.0Hydroxypropylcellulose (mg/mL) Crystalline Cellulose (PH102) 4.0 (mg/mL)Talc (mg/mL) 2.4 Relative Bitterness to 100% 42% 210% 138% 284% 218%192% Comparative Example 1 (%)9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

Test Example 8: Dissolution Test of Orally Disintegrating Tablet

Reagents shown in Table 12 were used to obtain orally disintegratingtablets on the basis of prescription shown in Table 13 in accordancewith procedures shown in Table 14. A dissolution test was performedunder conditions shown in Table 14, and results illustrated in FIG. 8were obtained.

TABLE 12 Molecular Component Weight Manufacturer Grade/Product NameMannitol Merck KGaA PERTECK M200 Low-substituted Shin-Etsu L-HPC NBD-022Hydroxypropyl- Chemical Co., cellulose Ltd. Sodium Stearyl JRS PharmaPruv Fumarate L-arginine 174.2 Merck KGaA Emprove Calcium 100.09 BihokuFunka Precipitated Calcium Carbonate Kogyo Co., Carbonate A Ltd.Magnesium 40.3 Tomita Magnesium Oxide XE, Oxide Pharmaceutical JapanesePharmacopoeia Co., Ltd. Aminoalkyl Evonik Rohm Eudragit EPO MethacrylateGmbH Copolymer E

TABLE 13 Component mg/Tab g/batch Lenvatinib Mesylate 12.25 0.245Mannitol 197.75 3.955 Low-substituted Hydroxypropylcellulose 25.0 0.500Sodium Stearyl Fumarate 2.5 0.050 Additive 12.5 0.250 Total 250.0 5.00Additive Lot Mannitol Example 20 L-arginine Example 21 Calcium CarbonateExample 22 Magnesium Oxide Example 23 Aminoalkyl Methacrylate CopolymerE Example 24

TABLE 14 Step Operation Mixing Well mixed with mortar and pestleTableting A tablet of 250 mg with a diameter of 9 mm and 9 mmR iscompression molded at 10 kN using a compression moldability analyzer(Tabflex, Okada Seiko Co., Ltd.). Dissolution Test NTR-6100A, ToyamaSangyo Co., Ltd. 0.1N HCl (USP) 900 mL Paddle 50 rpm (~60 min), then 250rpm (~75 min) 10 mg (per tablet) of E7080 in the free form is put.Absorbance at 308 nm (reference 400 nm) of test solution having passedthrough a filter (Fine Filter F72, Forte Grow Medical Co., Ltd.) ismeasured with a cell having a length of 10 mm to calculate dissolutionrate (UV-1700, Shimadzu Corporation). Average obtained when n = 2 isdescribed.

A list of reagents used in preparation and bitterness measurement ofexamples and comparative examples described below but not listed inTable 1 is shown in Table 15.

TABLE 15 Molecular Component Weight Manufacturer Grade/Product Name No.4 CAPSUGEL Japanese Hypromellose Pharmacopoeia Capsule Sodium 105.99Takasugi Food Additive Carbonate Pharmaceutical Co., Ltd. AmmoniumTakasugi Food Additive Carbonate Pharmaceutical Co., Ltd. Sodium 84.01Wako Pure G.R. Hydrogencarbonate Chemical Industries, Ltd. Potassium100.12 Takasugi G.R. Hydrogencarbonate Pharmaceutical Co., Ltd.Magnesium 591.26 Mallinckrodt Magnesium Stearate Stearate Calcium Oxide56.08 Ube Material CSQ Industries, Ltd. Calcium Hydroxide 74.09 WakoPure G.R. Chemical Industries, Ltd. Sodium Hydroxide 40.00 Wako PureG.R. Chemical Industries, Ltd. Alumina Kyowa Sanarumin MagnesiumChemical Hydroxide Industry Co., Ltd. L-histidine 155.15 Wako Pure G.R.Chemical Industries, Ltd. L-arginine 174.2 Merck EMPROVE Synthetic KyowaAlcamac B Hydrotalcite Chemical Industry Co., Ltd. Magnesium TomitaHeavy Silicate Pharmaceutical Co., Ltd. Magnesium Tomita AluminosilicatePharmaceutical Co., Ltd. Calcium N/A Tokuyama Flow Light RE SilicateCorporation

Text Example 9: Bitterness Suppressing Effect of Composition ComprisingLenvatinib Mesylate

In the same manner as in Test Example 2, the bitterness of measurementsamples of Example 25 and Comparative Example 1 respectively havingcompositions shown in Table 16 was measured.

The measurement sample of Example 25 was prepared by the followingmethod. A capsule comprising lenvatinib mesylate, the composition ofwhich is shown in Table 16, was prepared by filling a No. 4 hypromellosecapsule with 100 mg of the composition comprising lenvatinib mesylateprepared in Example 18. To the capsule, a 10 mM potassium chlorideaqueous solution was added to a concentration shown in Table 16, and theresultant was stirred for 30 minutes with a stirrer. After stirring, thecentrifugation operation described in (3) of Test Example 2 wasperformed to collect a supernatant portion as a measurement sample.

The measurement result of the relative bitterness of Example 25 toComparative Example 1 is illustrated in FIG. 9. As a result, it wasfound that the relative bitterness of Example 25 to Comparative Example1 was 70% or less.

TABLE 16 Example Comparative 25 Example 1 Lenvatinib Mesylate (mg/mL)9.8^(a)) 9.8 Calcium Carbonate (mg/mL) 26.4^(a)) Mannitol(mg/mL)7.0^(a)) Crystalline Cellulose (PH101) (mg/mL) 8.0^(a))Hydroxypropylcellulose (mg/mL) 2.4^(a)) Low-substitutedHydroxypropylcellulose 20.0^(a)) (mg/mL) Crystalline Cellulose (PH102)(mg/mL) 4.0 Talc(mg/mL) 2.4 No. 4 Hypromellose Capsule (Capsule/mL) 0.8Relative Bitterness to Comparative 22% 100% Example 1 (%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

a) is equivalent to 73.6 mg of the sized granule

Test Example 10: Bitterness Suppressing Effect of Various Low MolecularWeight Compounds

In the same manner as in Test Example 2, measurement samples of Examples26 to 39 and Comparative Example 1 respectively having compositionsshown in Table 17 and Table 18 were prepared to measure the bitternessof the samples.

The measurement results of the relative bitterness of Examples 26 to 32to Comparative Example 1 are illustrated in FIG. 10. The measurementresults of the relative bitterness of Examples 33 to 39 to ComparativeExample 1 are illustrated in FIG. 11. As a result, it was found that therelative bitterness of Examples 26 to 39 to Comparative Example 1 was70% or less.

TABLE 17 Comp Ex 26 Ex 27 Ex 28 Ex 29 Ex 30 Ex 31 Ex 32 Ex 1 LenvatinibMesylate (mg/mL) 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 Sodium Carbonate(mg/mL) 1.39 Ammonium Carbonate 1.32 (mg/mL) Sodium Hydrogencarbonate1.10 3.31 (mg/mL) Potassium Hydrogencarbonate 1.31 3.94 (mg/mL)Magnesium Stearate (mg/mL) 7.76 Molar Ratio 0.70 1.4^(a)) 0.70 0.70 2.12.1 0.70 (Additive/Lenvatinib Mesylate) Relative Bitterness to 7% 11%10% 12% 11% 12% 64% 100% Comparative Example 1 (%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

a) On the basis of a mass composition described in a certificate ofanalysis issued by the manufacturer, a molar ratio between an ammoniumion and lenvatinib mesylate was calculated.

TABLE 18 Comp Ex 33 Ex 34 Ex 35 Ex 36 Ex 37 Ex 38 Ex 39 Ex 1 LenvatinibMesylate (mg/mL) 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 Calcium Oxide (mg/mL)0.74 Calcium Hydroxide (mg/mL) 0.97 Sodium Hydroxide (mg/mL) 0.52Alumina Magnesium 1.06 Hydroxide (mg/mL) L-histidine (mg/mL) 2.04L-arginine(mg/mL) 2.29 Synthetic Hydrotalcite 1.03 (mg/mL) Molar Ratio0.70 0.70 0.70 0.70^(a)) 0.70 0.70 0.70^(a)) 0.70 (Additive/LenvatinibMesylate) Relative Bitterness to 33% 34% 17% 50% 14% 17% 70% 100%Comparative Example 1 (%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

a) On the basis of a mass composition described in a certificate ofanalysis issued by the manufacturer, a molar ratio between a sum ofmetal ions (a sum of an aluminum ion and a magnesium ion) and lenvatinibmesylate was calculated.

Test Example 11: Bitterness Suppressing Effect of Various Silicic AcidCompounds

In the same manner as in Test Example 2, measurement samples of Examples40 to 42 and Comparative Example 1 respectively having compositionsshown in Table 19 were prepared to measure the bitterness of thesamples.

The measurement results of the relative bitterness of Examples 40 to 42to Comparative Example 1 are illustrated in FIG. 12. As a result, it wasfound that the relative bitterness of Examples 40 to 42 to ComparativeExample 1 was 70% or less.

TABLE 19 Example Example Example Comparative 40 41 42 Example 1Lenvatinib Mesylate  9.8  9.8  9.8 9.8 (mg/mL) Magnesium Silicate 13.2(mg/mL) Magnesium 13.2 Aluminosilicate (mg/mL) Calcium Silicate 13.2(mg/mL) Relative Bitterness 11% 13% 44% 100% to Comparative Example 1(%)

9.8 mg/mL of lenvatinib mesylate is equivalent to 8 mg/mL of a free formof lenvatinib.

Suspension Comprising Lenvatinib or Salt Thereof and AdministrationMethod

a. Preparation of Suspension Using Vial and Administration Method

Water or an apple juice (100% juice manufactured by Dole Food Company,Inc.), a screw cap, a 20 mL vial (manufactured by Nichidenrika-GlassCo., Ltd.), and a syringe (20 mL, manufactured by Baxa Corporation) wereprepared.

Capsules described in Examples 1 to 3 of U.S. Patent ApplicationPublication No. 2012/0077842 were put in the 20 mL vial (specifically,one to five capsules were put in the vial).

3 mL of water or the apple juice was poured into the vial with the 20 mLsyringe.

The vial was closed with the screw cap, and was allowed to stand stillfor about 10 minutes.

After standing for 10 minutes, the vial was shaken for about 3 minutesto dissolve capsule shell and suspend a granule, and the cap of the vialwas removed to administer 3 mL of the thus obtained suspension containedin the vial to a patient.

Rinsing Step

After administering 3 mL of the suspension from the vial, another fresh20 mL syringe was used to pour 2 mL of water or the apple juice into thevial.

After closing the vial with the screw cap, the vial was shaken tentimes, and the cap of the vial was removed to administer 2 mL of theresultant rinsing solution contained in the vial to the patient.

The total amount of the suspension and the rinsing solution to beadministered per one to five capsules was 5 mL.

b. Preparation of Suspension Using Syringe and Administration Method

Water or an apple juice (100% juice manufactured by Dole Food Company,Inc.), a cap, and a syringe (20 mL, manufactured by Baxa Corporation)were prepared.

The capsules described in Examples 1 to 3 of U.S. Patent ApplicationPublication No. 2012/0077842 were put in the 20 mL syringe(specifically, one to five capsules put in the syringe). The tip of thesyringe was closed with the cap. 3 mL of water or the apple juicecollected using another fresh syringe was poured into the formersyringe.

A piston was pushed into the end of the syringe by about 2 cm, and thesyringe was allowed to stand still for about 10 minutes. After standingfor 10 minutes, the syringe was shaken for about 3 minutes to dissolvecapsule shell and suspend a granule. The cap was removed from thesyringe, the piston was slid to remove the air from the syringe, and 3mL of the thus obtained suspension was administered from the syringe toa patient.

Rinsing Step

After administering 3 mL of the suspension from the syringe, the cap wasattached to the syringe again.

2 mL of water or the apple juice was collected using another freshsyringe, and was poured into the capped syringe.

The piston was pushed into the end of the syringe by about 2 cm,followed by shaking ten times.

The cap was removed from the syringe, the piston was slid to remove theair from the syringe, and 2 mL of the resultant rinsing solution wasadministered to the patient.

The total amount of the suspension and the rinsing solution to beadministered per one to five capsules was 5 mL.

c. Preparation of Suspension Using Syringe Equipped with NG Tube andAdministration Method

Water, an NG tube (40 cm, 6 Fr, manufactured by Vygon), a cap and asyringe (20 mL, manufactured by Baxa Corporation) were prepared.

The capsules described in Examples 1 to 3 of U.S. Patent ApplicationPublication No. 2012/0077842 were put in the syringe (specifically, oneto five capsules were put in the syringe). The tip of the syringe wasclosed with the cap. 3 mL of water collected using another fresh syringewas poured into the former syringe.

A piston was pushed into the end of the syringe by about 2 cm, and thesyringe was allowed to stand still for about 10 minutes. After standingfor 10 minutes, the syringe was shaken for about 3 minutes to dissolvecapsule shell and suspend a granule. The cap was removed from thesyringe, and the piston was slid to remove the air from the syringe. TheNG tube was attached to the syringe, and 3 mL of the thus obtainedsuspension was administered through the NG tube to a patient.

Rinsing Step

After administering the suspension, the NG tube was removed from thesyringe, and the cap was attached to the syringe again.

2 mL of water was collected using another fresh syringe, and was pouredinto the capped syringe.

The piston was pushed into the end of the syringe by about 2 cm, andthen, the syringe was shaken ten times. The cap was removed from thesyringe, and the piston was slid to remove the air from the syringe. TheNG tube was attached to the syringe, and 2 mL of the resultant rinsingsolution was administered through the NG tube to the patient.

The total amount of the suspension and the rinsing solution to beadministered per one to five capsules was 5 mL.

Preparation of Suspension of Capsule Comprising Lenvatinib and StabilityThereof

Materials:

Screw cap and vial (20 mL, manufactured by Nichidenrika-Glass Co., Ltd.)

Cap and syringe (20 mL, manufactured by BAXA Corporation)

NG tube (40 cm, 6 Fr, manufactured by Vygon)

Apple juice (100%, manufactured by Dole Food Company, Inc.)

Sample Preparation

1-1 Preparation of Suspension (Using Vial)

A vial was charged with one 1, 4 or 10 mg lenvatinib capsule or fivecapsules of a total lenvatinib amount of 17 mg (namely, three 1 mgcapsules, one 4 mg capsule and one 10 mg capsule). 3 mL of water or theapple juice was added thereto using a syringe, and the vial was closedwith the cap. The resultant vial was allowed to stand still for about 10minutes, and then was shaken for about 3 minutes to dissolve capsuleshell. The thus obtained suspension was taken out of the vial, and wassubjected to dilution and centrifugation to prepare a sample liquid.

1-2 Rinsing of Vial (First Rinsing Step)

In order to check the effect of a rinsing step, after taking out 3 mL ofthe suspension, 2 mL of water or the apple juice was added using asyringe, the vial was closed with the cap and then shaken at least tentimes, and the resultant rinsing solution was taken out of the vial andsubjected to dilution and centrifugation to prepare a sample liquid.

1-3 Second Rinsing Step

After taking out 2 mL of the rinsing solution from the vial, 2 mL ofwater or the apple juice was added using a syringe, and the vial wasclosed with the cap. The resultant was shaken at least ten times, andthe resultant rinsing solution was taken out of the vial and thensubjected to dilution and centrifugation to prepare a sample liquid.

1-4 Preparation of Suspension (Using Syringe)

In the same manner as in the preparation method using the vial, a 20 mLsyringe was charged with one 1, 4 or 10 mg lenvatinib capsule or fivecapsules of a total lenvatinib amount of 17 mg (namely, three 1 mgcapsules, one 4 mg capsule and one 10 mg capsule). The syringe wasclosed with the cap, and after adding 3 mL of water or the apple juicethereto using another fresh syringe, a piston was pushed into the end ofthe syringe by about 2 cm, and the syringe was allowed to stand stillfor about 10 minutes. After standing for 10 minutes, the syringe wasshaken for about 3 minutes to dissolve capsule shell. The piston wasthen pushed into the syringe to remove the air from the syringe, and thethus obtained suspension was taken out of the syringe and then subjectedto dilution and centrifugation to prepare a sample liquid.

1-5 Rinsing of Syringe (First Rinsing Step)

In order to check the effect of a rinsing step, after taken out 3 mL ofthe suspension, 2 mL of water or the apple juice was added thereto usinganother fresh syringe, the syringe was closed with the cap and thenshaken at least ten times, and the resultant rinsing solution was takenout of the syringe and then subjected to dilution and centrifugation toprepare a sample liquid.

1-6 Second Rinsing Step

After taking out 2 mL of the rinsing solution from the syringe, 2 mL ofwater or the apple juice was added thereto with a syringe, and thesyringe was closed with the cap. The resultant was shaken at least tentimes, and the resultant rinsing solution was taken out of the vial andthen subjected to dilution and centrifugation to prepare a sampleliquid.

1-7 Preparation of Suspension (Using Syringe Equipped with NG Tube)

In the same manner as in the preparation method using the syringe, a 20mL syringe was charged with one 1, 4 or 10 mg lenvatinib capsule or fivecapsules of a total lenvatinib amount of 17 mg (namely, three 1 mgcapsules, one 4 mg capsule and one 10 mg capsule). The syringe wasclosed with the cap, and after adding 3 mL of water thereto usinganother fresh syringe, a piston was pushed into the end of the syringeby about 2 cm, and the syringe was allowed to stand still for about 10minutes. After standing for 10 minutes, the syringe was shaken for about3 minutes to dissolve capsule shell. The piston was then pushed into thesyringe to remove the air from the syringe, the NG tube was attachedthereto, and the thus obtained suspension was taken out of the syringethrough the NG tube and then subjected to dilution and centrifugation toprepare a sample liquid.

1-8 Rinsing of Syringe Equipped with NG Tube (First Rinsing Step)

In order to check the effect of a rinsing step, after taken out 3 mL ofthe suspension from the syringe through the NG tube, 2 mL of water wasadded thereto using another fresh syringe, the syringe was closed withthe cap and then shaken at least ten times, and the resultant rinsingsolution was taken out of the syringe through the NG tube and thensubjected to dilution and centrifugation to prepare a sample liquid.

1-9 Second Rinsing Step

After taking out 2 mL of the rinsing solution from the syringe throughthe NG tube, 2 mL of water was added thereto using another syringe, andthe syringe was closed with the cap. The resultant was shaken at leastten times, and the resultant rinsing solution was taken out of thesyringe through the NG tube and then subjected to dilution andcentrifugation to prepare a sample liquid.

1-10 Dilution and Centrifugation Step

The whole amount of each suspension of the 1 mg, 4 mg or 10 mg capsuleswas transferred to a 50 mL volumetric flask, and the whole amount of thesuspension of the 17 mg capsules (including three 1 mg capsules, one 4mg capsule and one 10 mg capsule) was transferred to a 200 mL volumetricflask, and the resultant was diluted with a diluent (methanol, water andsodium dihydrogen phosphate dihydrate in 800:200:1 (v/v/w)) to thevolume of the flask. The centrifugation was performed after extractionby stirring and an ultrasonic treatment in a water bath.

The final lenvatinib concentration of the suspensions of the 1 mg and 4mg capsules were respectively 0.02 mg/mL and 0.08 mg/mL.

As for the suspension of the 10 mg capsule, after performing thecentrifugation in the same manner as the suspensions of the 1 mg and 4mg capsules, 5 mL of a supernatant was transferred to a 10 mL flask andthen diluted with the diluent. The final lenvatinib concentration of thesuspension of the 10 mg capsule was 0.10 mg/mL.

As for the suspension of 17 mg capsules, after performing thecentrifugation in the same manner as the suspension of the 10 mgcapsule, 5 mL of a supernatant was transferred to a 20 mL flask and thendiluted with the diluent. The final lenvatinib concentration of thesuspension of the 17 mg capsules was 0.085 mg/mL.

Recovery of the lenvatinib was measured under HPLC conditions shown inTable 20.

TABLE 20 HPLC Waters Alliance Detection UV (Wavelength: 252 nm) ColumnYMC Pack-Pro C18 (4.6 mm × 7.5 cm, 3 μm) Column Temperature about 35° C.Sample Cooler about 5° C. Temperature Mobile Phase Water, Acetonitrile,Perchloric Acid (70%) (800:200:1, v/v/v) Flow Rate 1 mL/min (RetentionTime of Lenvatinib Peak: about 4 to 5 minutes) Injection Volume 5 μL (4,10, 17 mg Capsule), 10 μL (1 mg Capsule) Measurement Time 6 minutesafter injection

Results of Recovery of Lenvatinib

The recoveries of the suspensions of the 1, 4, 10 and 17 mg capsulesusing the vial, the syringe and the syringe equipped with the NG tubeare shown in Tables 21 to 24.

The selection of water or the apple juice caused no difference in therecovery. If the rinsing step was not performed, the recovery waslowered. There was no difference whether the rinsing step was performedonce or twice, and the recovery of 90% or more was attained if therinsing step was performed at least once.

TABLE 21 Water (room temperature) Apple Juice Syringe (room temperature)Vial Syringe (20 mL + Vial Syringe (20 mL) (20 mL) NG tube) (20 mL) (20mL) 3 mL (no rinsing) 92.4 99.2 88.0 88.5 93.6 (average, n = 3) RinsingOnce with 96.6 100.3 94.3 97.2 95.7 2 mL (average, n = 3) Rinsing Twicewith 97.2 100.4 94.7 98.3 96.0 2 mL (average, n = 3)

TABLE 22 Water (room temperature) Apple Juice Syringe (room temperature)Vial Syringe (20 mL + Vial Syringe (20 mL) (20 mL) NG tube) (20 mL) (20mL) 3 mL (no rinsing) 85.0 97.1 86.6 85.5 92.8 (average, n = 3) RinsingOnce with 96.3 98.8 99.6 95.5 95.9 2 mL (average, n = 3) Rinsing Twicewith 97.5 98.9 100.3 96.9 96.5 2 mL (average, n = 3)

TABLE 23 Water (room temperature) Apple Juice Syringe (room temperature)Vial Syringe (20 mL + Vial Syringe (20 mL) (20 mL) NG tube) (20 mL) (20mL) 3 mL (no rinsing) 85.5 96.9 89.0 84.5 93.8 (average, n = 3) RinsingOnce with 97.5 99.4 96.6 94.1 98.2 2 mL (average, n = 3) Rinsing Twicewith 98.9 99.6 97.3 95.4 98.7 2 mL (average, n = 3)

TABLE 24 Water (room temperature) Apple Juice Syringe (room temperature)Vial Syringe (20 mL + Vial Syringe (20 mL) (20 mL) NG tube) (20 mL) (20mL) 3 mL (no rinsing) 81.6 93.6 78.1 81.5 90.9 (average, n = 3) RinsingOnce with 95.0 95.9 93.8 93.0 94.3 2 mL (average, n = 3) Rinsing Twicewith 96.6 96.3 94.4 94.5 94.9 2 mL (average, n = 3)

Chemical Stability of Lenvatinib in Suspension

In accordance with the description of 1-1, each of 1 mg, 4 mg and 10 mgcapsules was suspended in 3 mL of water or the apple juice in a vial.The whole amount of the resultant suspension at the initial stage or 24hours after was transferred to a 50 mL volumetric flask, and a diluent(methanol, water and sodium dihydrogen phosphate dihydrate in 800:200:1(v/v/w)) was added thereto for dilution to the volume of the flask.Centrifugation was performed after extraction by stirring and anultrasonic treatment in a water bath. Each supernatant obtained afterthe centrifugation was measured under HPLC conditions shown in Table 25,and chemical stabilities at the initial stage and after 24 hours of thelenvatinib suspension in water or the apple juice are shown in Tables 26to 28 in the form of the amount of a detected impurity X.

As a result of the experiments, the amount of the impurity X was notincreased from the initial value even after 24 hours, and hence it wasfound that the lenvatinib suspension in water or the apple juice wasstable for 24 hours.

TABLE 25 HPLC Waters Alliance Detection UV (Wavelength: 252 nm) ColumnYMC Pack-Pro C18 (4.6 mm × 7.5 cm, 3 μm) Column Temperature about 35° C.Sample Cooler about 5° C. Temperature Mobile Phase A Water,Acetonitrile, Perchloric Acid (70%) (990:10:1, v/v/v) Mobile Phase BAcetonitrile, Water, Perchloric Acid (70%) (900:100:1, v/v/v) Flow Rate1 mL/min (Retention Time of Lenvatinib Peak: about 13 to 14 minutes)Time Mobile Phase A Mobile Phase B Gradient Program (min) (%) (%) 0.00100 0 22.00 55 45 25.00 55 45 25.01 100 0 30.00 100 0 Injection Volume20 μL (1 mg Capsule), 5 μL (4 mg Capsule), 2 μL (10 mg Capsule)Measurement Time 30 minutes after injection

TABLE 26 Suspension Water Apple Juice (1 mg/3 mL) Initial After 24 HoursInitial After 24 Hours n = 1 0.05% or less 0.05% or less 0.05% or less0.05% or less n = 2 0.05% or less 0.05% or less 0.05% or less 0.05% orless n = 3 0.05% or less 0.05% or less 0.05% or less 0.05% or less

TABLE 27 Suspension Water Apple Juice (4 mg/3 mL) Initial After 24 HoursInitial After 24 Hours n = 1 0.05% or less 0.05% or less 0.05% or less0.05% or less n = 2 0.05% or less 0.05% or less 0.05% or less 0.05% orless n = 3 0.05% or less 0.05% or less 0.05% or less 0.05% or less

TABLE 28 Suspension Water Apple Juice (10 mg/3 mL) Initial After 24Hours Initial After 24 Hours n = 1 0.05% or less 0.05% or less 0.05% orless 0.05% or less n = 2 0.05% or less 0.05% or less 0.05% or less 0.05%or less n = 3 0.05% or less 0.05% or less 0.05% or less 0.05% or less

Viscosity

In accordance with the description of 1-4, each of 1, 4 and 10 mglenvatinib capsules or each combination of capsules shown in Table 30was suspended in a syringe by using 3 mL of water. Results ofviscosities (unit: η/mPas) of the respective suspensions obtained bymeasurement performed under conditions shown in Table 29 are shown inTable 30. There was no difference in the viscosity whethermoisture-proof packed capsules were stored for 6 months at 5° C. or at40° C./75% RH (relative humidity). It is noted that the capsules werestored under the aforementioned conditions after moisture-proofpackaging.

TABLE 29 Viscometer Viscotester 550 rotational Viscometer (Thermoscientific) Rotational Speed 90 rpm Measurement Time 180 seconds Numberof Times of 100 Times Sampling Sample Temperature about 25° C.

TABLE 30 Conditions for Storing 1, 4 or 10 mg Capsule Suspension 5° C.40° C./75% RH 6 months  1 mg/3 mL water 3.4 2.8  4 mg/3 mL water 2.9 3.110 mg/3 mL water 3.3 3.2 17 mg (*1)/3 mL water 95.2 89.9 23 mg (*2)/3 mLwater 109.0 109.2 24 mg (*3)/3 mL water 21.5 21.4 (*1): 1 mg 3 capsule,4 mg 1 capsule, 10 mg 1 capsule (*2): 1 mg 3 capsules, 10 mg 2 capsules(*3): 4 mg 1 capsule, 10 mg 2 capsules

NG Tube Passability Test

In accordance with the description of 1-7, each of 1, 4 and 10 mglenvatinib capsules or each combination of capsules shown in Table 30was suspended in a syringe by using 3 mL of water, and then an NG tubewas connected to the syringe. Results of an NG tube passability testthus performed are shown in Table 31. Moisture-proof packaged capsulesstored for 6 months at 5° C. and at 40° C./75% RH (relative humidity)both passed through the tubes, and there was no difference in the tubepassability. It is noted that the capsules were stored under theaforementioned conditions after moisture-proof packaging.

TABLE 31 Conditions for Storing 1, 4 or 10 mg Capsule Suspension 5° C.40° C./75% RH 6 months  1 mg/3 mL water passed passed  4 mg/3 mL waterpassed passed 10 mg/3 mL water passed passed 17 mg (*1)/3 mL waterpassed passed 23 mg (*2)/3 mL water passed passed 24 mg (*3)/3 mL waterpassed passed (*1): 1 mg 3 capsules, 4 mg 1 capsule, 10 mg 1 capsule(*2): 1 mg 3 capsules, 10 mg 2 capsules (*3): 4 mg 1 capsule, 10 mg 2capsules

1. A method for suppressing bitterness of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamide,comprising mixing4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof and a basic substance. 2.The method according to claim 1, wherein 0.01 to 50 parts by weight ofthe basic substance is mixed per 1 part by weight of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.
 3. The method accordingto claim 1, wherein 0.16 to 80 mol of the basic substance is mixed per 1mol of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.
 4. The method accordingto claim 1, wherein the basic substance is a basic oxide, a basiccarbonate or a basic hydroxide.
 5. The method according to claim 1,wherein the basic substance is calcium carbonate or magnesium oxide. 6.The method according to claim 1, wherein the basic substance is calciumcarbonate.
 7. The method according to claim 1, wherein thepharmaceutically acceptable salt is a mesylate.
 8. A pharmaceuticalcomposition, comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance inan amount effective for suppressing bitterness.
 9. A pharmaceuticalcomposition, comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, the pharmaceuticalcomposition comprising means for mixing a basic substance forsuppressing bitterness.
 10. A pharmaceutical composition, comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof and a basic substance, thepharmaceutical composition having bitterness suppressed.
 11. Thepharmaceutical composition according to claim 8, comprising 0.01 to 50parts by weight of the basic substance per 1 part by weight of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.
 12. The pharmaceuticalcomposition according to claim 8, wherein 0.16 to 80 mol of the basicsubstance is mixed per 1 mol of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.
 13. The pharmaceuticalcomposition according to claim 8, wherein the basic substance is a basicoxide, a basic carbonate or a basic hydroxide.
 14. The pharmaceuticalcomposition according to claim 8, wherein the basic substance is calciumcarbonate or magnesium oxide.
 15. The pharmaceutical compositionaccording to claim 8, wherein the basic substance is calcium carbonate.16. The pharmaceutical composition according to claim 8, wherein thepharmaceutically acceptable salt is a mesylate.
 17. The pharmaceuticalcomposition according to claim 8, in a dosage form of an orallydisintegrating tablet, a chewable preparation, an effervescent tablet, adispersible tablet, a soluble tablet, a syrup, a preparation for asyrup, a troche, or an oral liquid preparation.
 18. The pharmaceuticalcomposition according to claim 8, being a preparation that can besuspended in an aqueous solvent upon an administration to prepare asuspension.
 19. A bitterness suppressing agent, comprising a basicsubstance, for4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof.
 20. The bitternesssuppressing agent according to claim 19, wherein the basic substanceadded is in an amount of 0.01 to 50 parts by weight per 1 part by weightof4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.
 21. The bitternesssuppressing agent according to claim 19, wherein the basic substanceadded is in an amount of 0.16 to 80 mol per 1 mol of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof.
 22. The bitternesssuppressing agent according to claim 19, wherein the basic substance isa basic oxide, a basic carbonate or a basic hydroxide.
 23. Thebitterness suppressing agent according to claim 19, wherein the basicsubstance is calcium carbonate or magnesium oxide.
 24. The bitternesssuppressing agent according to claim 19, wherein the basic substance iscalcium carbonate.
 25. The bitterness suppressing agent according toclaim 19, wherein the pharmaceutically acceptable salt is a mesylate.26. A method for administering a suspension comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance,the method comprising: 1) suspending a pharmaceutical compositioncomprising 1 to 24 mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof, and the basic substancein an aqueous solvent in a vessel; 2) administering a suspensionobtained in 1) to a patient from the vessel; 3) rinsing the vessel withan aqueous solvent; and 4) administering a rinsing solution obtained in3) to the patient.
 27. The method according to claim 26, wherein 1)comprises: i) pouring the aqueous solvent in the vessel, ii) allowingthe vessel to stand; and iii) shaking the vessel.
 28. The methodaccording to claim 26, wherein the pharmaceutical composition issuspended in 1 to 10 mL of the aqueous solvent in 1).
 29. The methodaccording to claim 28, wherein the pharmaceutical composition issuspended in about 3 mL of the aqueous solvent in 1).
 30. The methodaccording to claim 26, wherein the vessel is rinsed with 1 to 10 mL ofthe aqueous solvent in 3).
 31. The method according to claim 30, whereinthe vessel is rinsed with about 2 mL of the aqueous solvent in 3).
 32. Amethod for treating a cancer, comprising administering a suspensioncomprising 1 to 24 mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance.33. A method for treating a cancer, comprising administering asuspension comprising4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor a pharmaceutically acceptable salt thereof, and a basic substance,the method comprising: 1) suspending, in an aqueous solvent in a vessel,a pharmaceutical composition comprising 1 to 24 mg of4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxyamideor the pharmaceutically acceptable salt thereof, and the basic substance; 2) administering a suspension obtained in 1) to a patient fromthe vessel; 3) rinsing the vessel with an aqueous solvent; and 4)administering a rinsing solution obtained in 3) to the patient.